Process for the preparation of N-[(3-aminooxetan-3-yl)methyl]-2-(1,1-dioxo-3,5-dihydro-1,4-benzothiazepin-4-yl)-6-methyl-quinazolin-4-amine

ABSTRACT

The present invention relates to a novel process for the preparation of a compound of the formula (I): 
                         
and pharmaceutically acceptable acid addition salts thereof, which is useful for prophylaxis and treatment of respiratory syncytial virus (RSV) infection in mammal or human being.

RELATED APPLICATIONS

This application is a continuation of International Application PCT/EP2015/051066, having an international filing date of Jan. 21, 2015, and which claims benefit under 35 U.S.C § 119 to PCT/CN2014/071331 having an international filing date of Jan. 24, 2014. The entire contents of these applications are hereby incorporated herein by reference.

The present invention relates to a process for the preparation of a compound of the formula (I):

and pharmaceutically acceptable addition salts thereof, which is useful for prophylaxis and treatment of respiratory syncytial virus (RSV) infection in mammal or human being.

Another aspect of the present invention relates to a novel process for the preparation of a compound of the formula (V):

wherein R is C₁₋₆alkyl, C₁₋₆alkoxyphenyl-C_(x)H_(2x)— or phenyl-C_(x)H_(2x)—. Compound of the formula (V) is important intermediate in the synthesis and manufacture of pharmaceutically active compound of formula (I) as described in patent as described in patent WO2013020993 A1.

BACKGROUND OF THE INVENTION

The patent WO2013020993 A1 disclosed synthetic approaches to obtain compound of formula (I). However, according to the synthetic approach in patent WO2013020993 A1, deprotection of one of the intermediates, 3-(aminomethyl)-N,N-dibenzyl-oxetan-3-amine, for synthesizing compound of formula (I) by hydrogenation with palladium on carbon will lead to heavy metal residual issue, which is not suitable for process chemistry and large scale manufacture. In addition, another intermediate, tert-butyl [(3-aminooxetan-3-yl)methyl]carbamate, for synthesizing compound of formula (I) suffers from instability as the primary amine.

In this invention, a simple and effective synthetic approach is developed to synthesize compounds of formula (I). This synthetic approach can be applied on technical scale and allows to obtain the product in a good yield, desired purity and stable form without using heavy metal catalyst.

DETAILED DESCRIPTION OF THE INVENTION Definitions

As used herein, the term “C₁₋₆alkyl” signifies a saturated, linear- or branched chain alkyl group containing 1 to 6, particularly 1 to 5 carbon atoms, for example as methyl, ethyl, n-propyl, isopropyl, n-butyl, s-butyl, isobutyl, tert-butyl, n-pentyl, 3-methylbutyl, 1,1-dimethylpropyl, n-hexyl, 2-ethylbutyl and the like. Particular “C₁₋₆alkyl” groups are tert-butyl and 1,1-dimethylpropyl.

The term “C_(x)H_(2x)” signifies a saturated, linear- or branched chain alkyl group containing 1 to 6, particularly 1 to 4 carbon atoms.

The term “C₁₋₆alkoxy” signifies a group C₁₋₆alkyl-O—, wherein the “C₁₋₆alkyl” is as defined above, for example methoxy, ethoxy, propoxy, iso-propoxy, n-butoxy, iso-butoxy, 2-butoxy, tert-butoxy and the like. Particular “C₁₋₆alkoxy” groups are methoxy and ethoxy and more particularly methoxy.

The term “C₁₋₆alkoxyphenyl” signifies a phenyl substituted by C₁₋₆alkoxy group as defined above at ortho, meta or para position. Particular “C₁₋₆alkoxyphenyl” group is 4-methoxyphenyl.

The term “amino” refers to primary (—NH₂), secondary (—NH—) or tertiary amino

The term “hydroxy” refers to the group —OH.

The term “HA” refers to organic or inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, acetic acid, L-tartaric acid, citric acid, L-lactic acid, maleic acid, fumaric acid, succinic acid, methanesulfonic acid, benzenesulfonic acid, benzoic acid, p-toluenesulfonic acid, oxalic acid, p-nitrobenzoic acid, salicylic acid and 4-chlorobenzoic acid and the like.

The term “acid addition salt” refers to conventional acid addition salts that are formed from suitable non-toxic organic or inorganic acids. Acid addition salts include for example those derived from organic or inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, acetic acid, L-tartaric acid, citric acid, L-lactic acid, maleic acid, fumaric acid, succinic acid, methanesulfonic acid, benzenesulfonic acid, benzoic acid, p-toluenesulfonic acid, oxalic acid, p-nitrobenzoic acid, salicylic acid and 4-chlorobenzoic acid and the like.

TABLE 1 Abbreviations Ac₂O: acetic anhydride AcOH: acetic acid CD3Cl-d3: deuterated chloroform DCM: Dichloromethane DMF: Dimethylformamide DMSO-d6: deuterated dimethylsulfoxide DPPA: diphenylphosphoryl azide EtOAC: ethyl acetate EtOH: Ethanol HPLC: high performance liquid chromatography hr or hrs: hour or hours Hz: Hertz kg: Kilogram L: Liter METHANOL-d4: deuterated methanol MHz: Megahertz mins: Minutes mmol: Millimole MS (ESI): mass spectroscopy (electron spray ionization) MTBE: methyl tert-butyl ether NaOH: sodium hydroxide NMM: 4-methylmorpholine NMR: nuclear magnetic resonance obsd.: Observed sat. Saturated TEA: Triethylamine TEMPO: 2,2,6,6-tetramethylpiperidinooxy TFA: trifluoroacetic acid THF: Tetrahydrofuran

The problems in WO2013020993 A1 are solved according to present invention by a process for preparing the compounds of formula (I) shown in scheme 1:

wherein R is C₁₋₆alkyl, C₁₋₆alkoxyphenyl-C_(x)H_(2x)— or phenyl-C_(x)H_(2x)—.

The invention relates to a process for the preparation of a compound of the formula (I):

and pharmaceutically acceptable addition salts thereof, comprising the following steps: step a) oxidation of [3-(bromomethyl)oxetan-3-yl]methanol of formula (II) to form a compound of formula (III),

step b) conversion of carboxy group of a compound of formula (III) to carbamate to form a compound of formula (IV)

wherein R is C₁₋₆alkyl, C₁₋₆alkoxyphenyl-C_(x)H_(2x)— or phenyl-C_(x)H_(2x)—; step c) amination of a compound of formula (IV) to form a compound of formula (V)

wherein R is as defined above; step d) salt formation of a compound of formula (V) with an acid to form a compound of formula (VI)

wherein R is as defined above; step e) substitution reaction of a compound of formula (VI) with a compound of formula (IX) to give a compound of formula (VII)

wherein R is as defined above; step f) substitution reaction of a compound of formula (VII) with a compound of formula (X) to give a compound of formula (VIII)

wherein R is as defined above; step g) comprises deprotection of a compound of formula (VIII) to give a compound of formula (I)

-   -   and if necessary, form a pharmaceutically acceptable addition         salt.

The synthesis process steps (a), (b) and (c) result in compound of formula (V) which is a novel and is another important aspect of the present invention.

A detailed description of present invention of process steps is as following:

step a) comprises preparation of carboxylic acid of formula (III) by oxidizing [3-(bromomethyl)oxetan-3-yl]methanol of formula (II)

This reaction is performed with an oxidant at a reaction temperature range between 0° C. and 100° C., particularly between 15° C. to 25° C. The order of addition of reactants can be compelled by convenience.

The reaction can be conducted in various solvents, in particular, the reaction solvent is water, acetonitrile, dichloromethane, ethyl acetate or isopropyl acetate; or a co-solvent which is a mixture of two or more kinds of solvents selected from water, acetonitrile, dichloromethane, ethyl acetate and isopropyl acetate. More particular solvent is a co-solvent of water and acetonitrile.

The oxidant used in this reaction is sodium hypochlorite, potassium permanganate, 2,2,6,6-tetramethylpiperidinooxy or pyridinium chlorochromate; or a co-oxidant which is a mixture of two or more kinds of oxidants selected from sodium hypochlorite, potassium permanganate, 2,2,6,6-tetramethylpiperidinooxy and pyridinium chlorochromate. Particular oxidant is a co-oxidant of 2,2,6,6-tetramethylpiperidinooxy and sodium hypochlorite. The oxidation reaction is as a rule finished after 1 to 24 hours, particularly 4 to 6 hours.

step b) comprises the conversion of carboxylic acid of formula (III) to carbamate of formula (IV) through Curtius rearrangement.

The reaction is performed with an azide reagent and a base in an organic solvent and followed by adding an alcohol at temperature range of 0° C. and 100° C., particularly 80° C.

In this step, a compound of formula (III) is mixed with an azide reagent, particularly diphenylphosphoryl azide, and a base in an organic solvent to form an active intermediate 3-(bromomethyl)-3-isocyanato-oxetane, which can be further converted to carbamates of formula (IV) by adding various alcohols.

The base used in this reaction is triethylamine, diisopropylethylamine or 4-methyl morpholine, more particularly 4-methyl morpholine.

The reaction can be conducted in many organic solvents. In particular, the solvent used in step b) is acetonitrile, toluene, chlorobenzene, dichloromethane. More particular solvent is toluene.

The reaction temperature lies in the range of 0° C. and 100° C., particularly 80° C.

Typically, the alcohol used in step b) is tert-butanol, 2-methyl-2-butanol, benzyl alcohol or 4-methoxyphenylmethanol, particularly 4-methoxyphenylmethanol.

step c) comprises amination of compound of formula (IV) to form an amino compound of formula (V).

The reaction is performed with an amination agent, at reaction temperature range of 0° C. and 60° C., particularly in the rage of 25° C. and 30° C.

In order to form a primary amine, compound of formula (IV) and an amination reagent, particularly liquid ammonia, are charged to an autoclave to give the compound of formula (V).

Reaction temperature as a rule lies in the range of 0° C. and 60° C., particularly in the rage of 25° C. and 30° C.

The reaction is generally finished after 1 to 24 hours, particularly 8 hours.

step d) comprises salt formation of a compound of formula (V) with an acid to form a compound of formula (VI).

The acid used in this reaction includes various organic and inorganic acids, such as hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, acetic acid, L-tartaric acid, citric acid, L-lactic acid, maleic acid, fumaric acid, succinic acid, methanesulfonic acid, benzenesulfonic acid, benzoic acid, p-toluenesulfonic acid, oxalic acid, p-nitrobenzoic acid, salicylic acid and 4-chlorobenzoic acid and the like, more particularly 4-chlorobenzoic acid.

step e) comprises the substitution reaction of a compound of formula (VI) with a compound of formula (IX) to give a compound of formula (VII).

The reaction can be performed in an organic solvent. In particular, the reaction is performed in tetrahydrofuran, 2-methyltetrahydrofuran or acetonitrile, more particularly in tetrahydrofuran.

The particular reaction temperature range is between 10° C. and 30° C.

step f) comprises the substitution reaction of a compound of formula (VII) with a compound of formula (X) to give a compound of formula (VIII). This reaction is performed in an organic solvent with an acid catalyst in temperature range between 0° C. and 100° C., particularly between 60° C. and 80° C.

The reaction is performed in an organic solvent. In particular, the reaction is performed in tetrahydrofuran, 2-methyltetrahydrofuran, acetonitrile, toluene, methanol, ethanol or iso-propanol, more particularly in ethanol.

Acid catalyst used in the reaction is hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, methanesulfonic acid or ammonium chloride, particularly is ammonium chloride.

step g) comprises the deprotection of a compound of formula (VIII) to give a compound of formula (I). The reaction is performed in an organic solvent with acid in temperature range between 0° C. and 100° C., particularly between 10° C. and 40° C.

The organic solvent used in the reaction is dichloromethane, ethylacetate, isopropyl acetate, tetrahydrofuran or dioxane, particularly dichloromethane.

The acid used in the reaction is hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, methanesulfonic acid or trifluoroacetic acid, particularly is or trifluoroacetic acid.

The invention is illustrated further by the following examples that are not be construed as limiting the invention in scope to the specific procedures described herein.

This invention further relates to a compound of formula (V):

wherein R is C₁₋₆alkyl, C₁₋₆alkoxyphenyl-C_(x)H_(2x)— or phenyl-C_(x)H_(2x)—.

This invention is also relates to a compound of formula (III):

EXAMPLES Example 1 Preparation of 3-(bromomethyl)oxetane-3-carboxylic acid

To a 100 ml flask was charged [3-(bromomethyl)oxetan-3-yl]methanol (17.3 g, 9.6 mmol) followed with 25 ml water and 5.3 mL of acetonitrile and TEMPO (153 mg, 0.96 mmol). The mixture was cooled to 10° C. 15.3 g sodium hypochloride (14%) was added over 10 min with the inner temperature maintained between 15° C. and 20° C. The reaction was stirred at room temperature till [3-(bromomethyl)oxetan-3-yl]methanol was consumed as monitored by HPLC. The resulted mixture was adjusted to pH 8-9 and extracted with 20 mL EtOAc twice. The aqueous layer was adjusted to pH 1-2 with 5N aqueous H₂SO₄ solution and extracted with dichloromethane. After removal of dichloromethane, 3-(bromomethyl)oxetane-3-carboxylic acid was obtained. MS obsd. (ESI⁺) [(M+H)⁺] 194. 1H NMR (400 MHz, METHANOL-d4) d ppm, 9.40-9.90 (s, 1H), 5.00-5.02 (d, J=6.8 Hz, 2H), 4.56-4.57 (d, J=6.8 Hz, 2H), 3.97 (s, 2H)

Example 2 Preparation of (4-methoxyphenyl)methyl N-[3-(bromomethyl)oxetan-3-yl]carbamate

To a Reactor 1 was charged 3-(bromomethyl)oxetane-3-carboxylic acid (1.2 kg, 6.15 mol) followed by 6.4 kg toluene. The reaction mixture was cooled to 5° C. Then NMM (0.72 kg, 7.12 mol) was added to this reaction mixture slowly. After the addition, the solution was stirred 10 mins at room temperature.

To Reactor 2 was charged diphenylphosphoryl azide (1.76 kg, 6.39 mol) followed by 3.2 kg toluene. The mixture was heated to 80° C. Solution in Reactor 1 was added to Reactor 2 dropwise. After the addition, the reaction mixture was stirred for 30 mins at 80° C. To the reaction mixture was then added 4-methoxyphenylmethanol (0.82 kg, 5.94 mol) in 1.58 kg toluene solution slowly. After the addition, the reaction mixture was allowed to hold for 75 mins at 80° C. The reaction was monitored using HPLC. After reaction completion, the mixture was cooled to room temperature, and was washed with 6.0 kg water, 6.24 kg 4% sodium carbonate aqueous solution and 3.0 kg water sequentially. The organic phase was concentrated till dryness under reduced pressure and the residue was recrystallized in n-heptane/ethanol. The suspension was separated via centrifuge and the wet cake was washed with 1 kg n-heptane. The wet cake was dried under vacuum oven for 24 hours to afford title compound 1.46 kg, yield 72%. MS obsd. (ESI⁺) [(M+H)⁺] 330. 1H NMR (400 MHz, CD3Cl-d3) d ppm 7.30-7.33 (d, J=8.4 Hz, 2H), 6.91-6.93 (d, J=8.4 Hz, 2H), 5.33 (s, 1H), 5.06 (s, 2H), 4.70-4.72 (d, J=6.4 Hz, 2H), 4.51-4.53 (d, J=6.4 Hz, 2H), 4.00 (s, 2H), 3.84 (s, 3H).

Example 3 Preparation of tert-butyl N-[3-(bromomethyl)oxetan-3-yl]carbamate

To a 50 ml flask was charged 3-(bromomethyl)oxetane-3-carboxylic acid (2.0 g, 10.3 mmol) followed by 20 mL of anhydrous t-butanol. The reaction mixture was cooled to 5° C. Then TEA (1.1 g, 11.3 mmol) was added. After the addition, DPPA (3.1 g, 10.8 mmol) was added in portions. The mixture was refluxed overnight. The organic phase was then concentrated till dryness under reduced pressure and the residue was dissolved in 30 ml EtOAc. The organic phase was washed with 10 mL Na₂CO₃ solution and 10 mL brine. After removal of solvents, tert-butyl N-[3-(bromomethyl)oxetan-3-yl]carbamate was obtained.

Example 4 Preparation of benzyl N-[3-(bromomethyl)oxetan-3-yl]carbamate

To a 100 ml flask was charged 3-(bromomethyl)oxetane-3-carboxylic acid (5.0 g, 25.6 mmol) followed by 50 mL of anhydrous toluene. Then TEA (2.87 g, 28.2 mmol) was added. After the addition of TEA, DPPA (7.64 g, 26.9 mmol) was added in portions. The mixture was heated at 65° C.-70° C. for 1 hour. To the reaction mixture was then added benzyl alcohol (4.2 g, 38.4 mmol) and heated at 80° C. for 2 hrs. The resulted mixture was cooled to room temperature and diluted with 50 ml EtOAc. The reaction mixture was washed with 30 mL water, 30 mL 10% Na₂CO₃ aqueous solution and 30 mL brine. The organic phase was concentrated to remove most of solvents under reduced pressure and 15 mL heptane was added. The suspension was stirred at room temperature for 2 hours and was separated by filtration. The wet cake was dried under vacuum oven to afford 4.95 g benzyl N-[3-(bromomethyl)oxetan-3-yl]carbamate.

Example 5 Preparation of 1,1-dimethylpropyl N-[3-(bromomethyl)oxetan-3-yl]carbamate

To a 250 ml flask was charged 3-(bromomethyl)oxetane-3-carboxylic acid (20.4 g, 100 mmol) followed by 120 mL of anhydrous toluene. NMM (12.1 g, 120 mmol) was added over 10 min. After the addition, DPPA (30.3 g, 110 mmol) in 80 ml toluene was added over 30 min. The mixture was heated at 80° C.-85° C. for 40 min. To the reaction mixture was then added t-amyl alcohol (44 g, 150 mmol) and heated at 80° C. for 3 hrs. The resulted mixture was cooled to room temperature and was washed with 100 mL water, 30 mL 10% Na₂CO₃ aqueous solution and 30 mL brine. The organic phase was concentrated in vacuum and the crude product was purified by flash chromatography. The product was slurried in heptane. After filtration and drying, 12.3 g 1,1-dimethylpropyl N-[3-(bromomethyl)oxetan-3-yl]carbamate was obtained.

Example 6 Preparation of (4-methoxyphenyl)methyl N-[3-(bromomethyl)oxetan-3-yl]carbamate

To a 10 L autoclave was charged (4-methoxyphenyl)methyl N-[3-(bromomethyl)oxetan-3-yl]carbamate (1.1 kg, 3.33 mol) and 5.5 L liquid ammonia. The reaction mixture was stirred at 25° C.-30° C. for 8 hours. Then the ammonia was released carefully. To the residue was added 5.5 L 2-methyltetrahydrofuran. The mixture was transferred into a separation funnel. To the mixture was then added 1.1 L 3N NaOH solution. The aqueous phase was extracted with 4.4 L 2-methyltetrahydrofuran. The combined organic phase was washed with 1.1 L saturated NaCl aqueous solution twice. After phase separation, organic phase was concentrated under vacuum to about 1 L. The crude residual was used directly without further purification.

Example 7 Preparation of (4-methoxyphenyl)methyl N-[3-(bromomethyl)oxetan-3-yl]carbamate

The titled compound is prepared in analogy to Example 6 by using benzyl N-[3-(bromomethyl) oxetan-3-yl]carbamate, which is prepared in Example 4, instead of (4-methoxyphenyl)methyl N-[3-(bromomethyl)oxetan-3-yl]carbamate,

Example 8 Preparation of 1,1-dimethylpropyl N-[3-(aminomethyl)oxetan-3-yl]carbamate

The titled compound is prepared in analogy to Example 6 by using 1,1-dimethylpropyl N-[3-(bromomethyl)oxetan-3-yl]carbamate, which is prepared in Example 5, instead of (4-methoxyphenyl)methyl N-[3-(bromomethyl)oxetan-3-yl]carbamate.

Example 9 Preparation of tert-butyl N-[3-(aminomethyl)oxetan-3-yl]carbamate

The titled compound is prepared in analogy to Example 6 by using tert-butyl N-[3-(bromomethyl)oxetan-3-yl]carbamate, which is prepared in Example 3, instead of (4-methoxyphenyl)methyl N-[3-(bromomethyl)oxetan-3-yl]carbamate.

Example 10 Preparation of (4-methoxyphenyl)methyl N-[3-(bromomethyl)oxetan-3-yl]carbamate 4-chlorobenzoic acid salt

To the residue from Example 6 was then added 4-chlorobenzoic acid (420 g, 2.68 mol) and 2 L MTBE. The mixture was stirred at 15° C.-25° C. for 14 hours. Vacuum filtration to collect the solid and the wet cake was washed with 1 L MTBE. The wet cake was dried under vacuum oven for 24 hours to afford 0.81 kg desired salt with yield 57.5%. MS obsd. (ESI⁺) [(M+H)⁺] 423. 1H NMR (400 MHz, DMSO-d6) δ ppm 8.32 (s, 1H), 7.88-7.91 (d, J=8.4 Hz, 2H), 7.42-7.45 (d, J=8.4 Hz, 2H), 7.29-7.31 (d, J=8.4 Hz, 2H), 6.90-6.92 (d, J=8.4 Hz, 2H), 4.94 (s, 2H), 4.54-4.56 (d, J=6.4 Hz, 2H), 4.44-4.45 (d, J=6.4 Hz, 2H), 3.75 (s, 3H), 3.19 (s, 2H).

Example 11 Preparation of (4-methoxyphenyl)methyl N-[3-[[(2-chloro-6-methyl-quinazolin-4-yl)amino]methyl]oxetan-3-yl]carbamate

To a 250 L glass-lined reactor was charged (4-methoxyphenyl)methyl N-[3-(bromomethyl)oxetan-3-yl]carbamate 4-chlorobenzoic acid salt (8.1 kg, 19.2 mol) and 61.6 kg tetrahydrofuran. To the solution was then added TEA (5.9 kg, 58.3 mol). The mixture was then cooled to 10° C.-15° C. To the mixture was then added 2,4-dichloro-6-methyl-quinazoline (3.99 kg, 18.7 mol) while control reaction temperature at 10° C.-30° C. The reaction mixture was then stirred at 22° C.-27° C. for 20 hours. HPLC was used to monitor the reaction. After reaction completion, the reaction mixture was concentrated in vacuum below 40° C. to 24.3-32.4 L over 3.5 hours while maintaining the bath temperature at 15° C.-25° C. To the residue was then added 80.2 kg water over 100 mins. The mixture was stirred at 15° C.-25° C. for 3.5 hours. The suspension was separated using centrifuge and washed with 48 kg water in four portions over 50 mins to afford 23.6 kg wet (4-methoxyphenyl)methyl N-[3-[[(2-chloro-6-methyl-quinazolin-4-yl)amino]methyl]oxetan-3-yl]carbamate.

To a 250 L glass-lined reactor was charged 23.6 kg wet (4-methoxyphenyl)methyl N-[3-[[(2-chloro-6-methyl-quinazolin-4-yl)amino]methyl]oxetan-3-yl]carbamate, 24.0 kg MTBE and 7.0 kg ethylacetate. The mixture was stirred at 15° C.-25° C. for 2.5 hours. The suspension was separated via centrifuge and washed with 6.0 kg MTBE. The wet cake was dried under vacuum oven at 38° C.-42° C. with a nitrogen bleed for 3 hours and then 40° C.-52° C. for 17 hours to afford 7.9 kg title compound with yield 92%. MS obsd. (ESI⁺) [(M+H)⁺] 443. 1H-NMR (400 Hz, DMSO-d6) d ppm 8.67-8.69 (t, J=5.6 Hz, 1H), 8.09 (s, 1H), 7.85 (s, 1H), 7.64-7.67 (m, 1H), 7.53-7.55 (m, 1H), 7.26-7.29 (d, J=8.4 Hz, 2H), 6.88-6.90 (d, J=8.4 Hz, 2H), 4.96 (s, 2H), 4.62-4.64 (d, J=6.4 Hz, 2H), 4.51-4.53 (d, J=6.4 Hz, 2H), 4.07-4.09 (d, J=6.4 Hz, 2H), 3.74 (s, 3H), 2.47 (s, 3H).

Example 12 Preparation of (4-methoxyphenyl)methyl N-[3-[[[2-(1,1-dioxo-3,5-dihydro-1,4-benzothiazepin-4-yl)-6-methyl-quinazolin-4-yl]amino]methyl]oxetan-3-yl]carbamate Preparation of intermediate formula (X): 2,3,4,5-Tetrahydro-1,4-benzothiazepine-1,1-dioxide

Step 1: Preparation of 2-phenylsulfanylethanamine

To a reactor was charged 56.1 kg of water followed by NaOH (7.0 kg, 175 mol). Start the mechanical stirrer until all NaOH dissolved to form a solution. Cool the solution to 25° C. and to the solution was added sodium thiophenoxide (50.7 kg, aqueous solution) and 2-chloroethylamine hydrochloride (17.7 kg, 153 mol). The mixture was stirred at 25° C. for 15 hours. HPLC was used to monitor the reaction. After reaction completion, the reaction mixture was extracted with 61.1 kg EtOAc twice. The combined organic phase was concentrated to about 92 L and used in next step without further purification.

Step 2: Preparation of N-(2-phenyl sulfanylethyl)acetamide

The residue of last step was heated to 45° C. and to the solution was slowly added AcOH (14.0 kg, 233 mol) while control the reaction temperature below 60° C. The reaction was monitored by HPLC. After reaction completion, the solution was cooled to 45° C. and concentrated under vacuum to remove 55 L EtOAc. The mixture was then cooled to below 25° C. and to the solution was slowly added 62.0 kg n-heptane. After addition, the suspension was cooled to 0° C. and held for 1 hour. The solid was collected by centrifuge.

The wet cake was dried under vacuum oven for 22 hours to afford 22.2 kg of N-(2-phenylsulfanylethyl) acetamide with 74% yield. MS obsd. (ESI⁺) [(M+H)⁺] 196. 1H-NMR (400 Hz, DMSO-d6) d ppm 8.07 (s, 1H), 7.18-7.40 (m, 5H), 3.21-3.26 (m, 2H), 2.99-3.03 (m, 2H), 1.80 (s, 3H).

Step 3: Preparation of 1-(3,5-dihydro-2H-1,4-benzothiazepin-4-yl)ethanone

To a reactor was charged N-(2-phenylsulfanylethyl) acetamide (22.2 kg, 114 mol) and 124.7 kg toluene. To the solution was then added paraformaldehyde (2.1 kg, 70 mol), methylsulfonic acid (10.9 kg, 113 mol) and Ac₂O (14.0 kg, 137 mol). The reaction mixture was heated to 75° C.-80 and to the reactor was then charged paraformaldehyde (4.9 kg, 163 mol) portionwise while control reaction temperature lower than 80° C. After the addition, the reaction mixture was heated to 100° C.-105° C. and held for 1 hour. The reaction was monitored by HPLC. After reaction completion, the reaction mixture was cooled to 30° C. and to the reactor was added 71.1 kg water. Phase separation and the organic solution was washed with 63.1 kg saturated NaHCO₃ aqueous solution followed by 63.1 kg brine solution. The organic phase was then concentrated under vacuum to remove all the organic solvent and the residue was used directly for next step without further purification.

Step 4: Preparation of 1-(1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)ethanone

To the left residue of last step was added 112.8 kg formic acid and 12.8 kg water. The mixture was cooled to 0° C. To the reaction mixture was slowly added 80.4 kg H₂O₂ (35%) while control reaction temperature lower than 10° C. After addition, the reaction mixture was stirred for 1 hour at 10° C. Then the reaction mixture was raised to 25° C. and stirred for 3 hours. The reaction was monitored using HPLC. After reaction completion, to the reaction mixture was added 177.3 kg water and 235.1 kg DCM. Phase separation and the aqueous layer was extracted with 165.9 kg DCM again. The combined organic phase was washed with 112.7 kg sat. Na₂SO₃ aqueous solution, 112.1 kg sat. Na₂CO₃ aqueous solution and 103.0 kg sat. NaCl aqueous solution. The organic phase was then concentrated under vacuum to remove all the organic solvent. The residue was then dispersed in 54.3 kg EtOH and stirred for 1 hour at 55° C.-65° C. The suspension was separated by centrifuge and the wet cake was dried under vacuum oven for 12 hours to afford 17.4 kg 1-(1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)ethanone with yield 64%. MS obsd. (ESI⁺) [(M+H)⁺] 240. 1H-NMR (400 Hz, DMSO-d6) d ppm 7.92-8.00 (m, 1H), 7.55-7.74 (m, 3H), 4.60-4.88 (m, 2H), 4.05 (brs, 2H), 3.48-3.70 (m, 2H), 3.53 (d, J=8.0 Hz, 3H).

Step 5: Preparation of 2,3,4,5-tetrahydro-1,4-benzothiazepine-1,1-dioxide

To a reactor was charged 1-(1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)ethanone (16.6 kg, 69.4 mol), 55.2 kg EtOH and 55. 8 kg NaOH aqueous solution (11.1 kg NaOH in 44.7 kg H₂O). The reaction mixture was heated to 74-79° C. and held for 24 hours at this temperature. The reaction was monitored using HPLC. After reaction completion, the mixture was cooled to 50° C.-55° C. and the organic solvent was removed under reduced pressure. To the reactor was then added 104.1 kg water and the mixture was cooled to 0° C.-7° C. and held for 1 hour. The suspension was separated using centrifuge and the wet cake was washed with 44.7 kg water twice. The wet cake was dried under vacuum oven for 24 hours to afford 9.9 kg 2,3,4,5-tetrahydro-1,4-benzothiazepine 1,1-dioxide with 72.3% yield. MS obsd. (ESI⁺) [(M+H)⁺] 198. 1H-NMR (400 Hz, DMSO-d6) d ppm 7.89 (dd, J=1.2, 7.6 Hz, 1H), 7.56 (t, J=7.6 Hz, 1H), 7.47 (t, J=7.6 Hz, 1H), 7.42 (d, J=7.6 Hz, 1H), 4.04 (s, 2H), 3.30-3.32 (m, 2H), 3.25-3.30 (m, 2H), 2.64 (s, 1H).

Preparation of (4-methoxyphenyl) methyl N-[3-[[[2-(1,1-dioxo-3,5-dihydro-1,4-benzothiazepin-4-yl)-6-methyl-quinazolin-4-yl]amino]methyl]oxetan-3-yl]carbamate

To a 250 L glass-lined reactor was charged 63 kg EtOH followed by (4-methoxyphenyl)methyl N-[3-[[(2-chloro-6-methyl-quinazolin-4-yl)amino]methyl]oxetan-3-yl]carbamate (7.8 kg, 17.6 mol), 2,3,4,5-tetrahydro-1,4-benzothiazepine-1,1-dioxide (3.89 kg, 19.7 mol) and ammonium chloride (49 g, 0.92 mol). The reaction mixture was stirred at 68° C.-72° C. for 20 hours. HPLC was used to monitor the reaction. After reaction completion, the reaction mixture was slowly cooled to 20° C.-25° C. The solids were collected by vacuum filtration and washed with 15.6 kg EtOH in two portions. The wet cake was dried in a vacuum oven with a nitrogen bleed at 38° C.-42° C. for about 4 hours and then heated to 50° C.-55° C. for 30 hours to afford 11.0 kg title compound with yield 88%. MS obsd. (ESI⁺) [(M+H)⁺] 604. 1H-NMR (400 Hz, DMSO) d ppm 9.57 (s, 1H), 8.14 (s, 1H), 7.93-7.95 (d, 1H, J=8), 7.68 (m, 3H), 7.57-7.58 (m, 1H), 7.22-7.23 (d, 2H, J=4), 7.68-7.69 (d, 2H, J=4), 4.98-5.17 (m, 2H), 4.26-4.68 (m, 5H), 3.74-4.1 (m, 3H), 3.4-3.46 (t, 1H, J=8), 2.51 (s, 3H), 2.39 (s, 3H).

Example 13 Preparation of N-[(3-aminooxetan-3-yl) methyl]-2-(1,1-dioxo-3,5-dihydro-1,4-benzothiazepin-4-yl)-6-methyl-quinazolin-4-amine

To a 250 L glass-lined reactor was charged N-[3-[[[2-(1,1-dioxo-3,5-dihydro-1,4-benzothiazepin-4-yl)-6-methyl-quinazolin-4-yl]amino]methyl]oxetan-3-yl]carbamate (10.8 kg, 24.6 mol) and 120 kg dichloromethane. To the mixture was then added 16.0 kg 1N NaOH solution in portions. After phase separation, the aqueous phase was extracted with 14.0 kg dichloromethane. The combined organic phase was washed with 25 kg 20% NaCl aqueous solution, then was transferred to a 100 L glass-lined reactor and concentrated to 30-35 L below 35° C. in vacuum to prepare Solution 1.

To another 250 L glass-lined reactor were charged with 26.0 kg dichloromethane and 16.0 kg trifluoroacetic acid. The mixture was cooled to 15° C.-20° C. and to the solution was added the titled Solution 1 in portions. The mixture was stirred for 30 mins at 15° C.-25° C. and then cooled to 0° C.-10° C. To the mixture was added 39.8 kg DMF and then the solution was concentrated to 62-65 L between 15° C.-30° C. in vacuum for over 16.5 hours to afford Solution 2.

To a 300 L glass-lined reactor was charged 128.3 kg 1.5N NaOH solution and cooled to 5° C.-7° C. To the reactor was then added 3.0 kg dimethylformamide followed by Solution 2. The suspension was stirred at 7° C.-11° C. for 30 mins. The solid was collected by vacuum filtration and washed with 101 kg water. Then the wet solid was charged into a 250 L glass-lined reactor followed by 54.0 kg EtOH. The mixture was heated to 74° C.-78° C. and stirred for 4.5 hours. The mixture was then cooled to 20° C.-25° C. The solid was collected by vacuum filtration and the wet cake was washed with 15.0 kg EtOH. The wet cake was dried in vacuum oven at 48° C.-52° C. with nitrogen bleed for 20 hours to afford 5.82 kg title compound with yield 85%. MS obsd. (ESI⁺) [(M+H)⁺] 440. 1H-NMR (400 Hz, METHANOL-D4) d ppm 7.98 (d, J=7.6 Hz, 1H), 7.86 (d, J=7.6 Hz, 1H), 7.73 (s, 1H), 7.60 (t, J=7.6 Hz, 1H), 7.32-7.47 (m, 3H), 5.53 (s, 2H), 4.58 (brs, 2H), 3.84 (s, 2H), 3.53 (t, J=4.8 Hz, 2H), 2.41 (2, 3H), 2.21 (m, 2H), 1.97-2.04 (m, 2H), 1.82-1.91 (m, 2H). 

The invention claimed is:
 1. Process for the preparation of a compound of the formula (I):

or pharmaceutically acceptable addition salts thereof, comprising the following steps: step a) oxidation of [3-(bromomethyl)oxetan-3-yl]methanol of formula (II) to form a compound of formula (III)

step b) conversion of carboxy group of a compound of formula (III) to carbamate to form a compound of formula (IV)

wherein R is C₁₋₆alkyl, C₁₋₆alkoxyphenyl-C_(x)H_(2x)— or phenyl-C_(x)H_(2x)—, wherein x is 1-6; step c) amination of a compound of formula (IV) to form a compound of formula (V)

wherein R is as defined above; step d) salt formation of a compound of formula (V) with an acid to form a compound of formula (VI)

wherein R is as defined above; step e) substitution reaction of a compound of formula (VI) with a compound of formula (IX)

to give a compound of formula (VII)

wherein R is as defined above; step f) substitution reaction of a compound of formula (VII) with a compound of formula (X)

to give a compound of formula (VIII)

wherein R is as defined above; step g) comprises deprotection of a compound of formula (VIII) to give a compound of formula (I)

and if necessary, form a pharmaceutically acceptable addition salt.
 2. A process according to claim 1, wherein R is tert-butyl, 1,1-dimethylpropyl, benzyl or 4-methoxyphenylmethyl.
 3. A process according to claim 1, wherein step a) is performed with an oxidant at a reaction temperature range between 0° C. and 100° C.
 4. A process according to claim 1, wherein step a) is performed in a solvent comprising water, acetonitrile, dichloromethane, ethyl acetate or isopropyl acetate; or a co-solvent which is a mixture of two or more kinds of solvents comprising water, acetonitrile, dichloromethane, ethyl acetate or isopropyl acetate.
 5. A process according to claim 3, wherein the oxidant comprises sodium hypochlorite, potassium permanganate, 2,2,6,6-tetramethylpiperidinooxy or pyridinium chlorochromate; or a co-oxidant which is a mixture of two or more kinds of oxidants comprising sodium hypochlorite, potassium permanganate, 2,2,6,6-tetramethylpiperidinooxy or pyridinium chlorochromate.
 6. A process according to claim 1, wherein step b) is performed with an azide reagent and a base in an organic solvent and followed by adding an alcohol at temperature range of 0° C. and 100° C.
 7. A process according to claim 6, wherein the azide reagent used in step b) is diphenylphosphoryl azide.
 8. A process according to claim 6, wherein the base used in step b) is triethylamine, diisopropylethylamine or 4-methyl morpholine.
 9. A process according to claim 6, wherein the solvent used in step b) is acetonitrile, toluene, chlorobenzene or dichloromethane.
 10. A process according to claim 6, wherein the alcohol used in step b) is tert-butanol, 2-methyl-2-butanol, benzyl alcohol or 4-methoxyphenylmethanol.
 11. A process according to claim 1, wherein step c) is performed with an amination agent, at reaction temperature range of 0° C. and 60° C.
 12. A process according to claim 11, wherein the amination agent used in step c) is liquid ammonia.
 13. A process according to claim 1, wherein step d) is performed in a solvent with an organic or inorganic acid at a temperature range of 0° C. and 60° C.
 14. A process according to claim 13, wherein the solvent used in step d) is tetrahydrofuran, 2-methyltetrahydrofuran, acetonitrile, ethylacetate or methyl tert-butyl ether.
 15. A process according to claim 13, wherein the acid used in step d) is hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, acetic acid, L-tartaric acid, citric acid, L-lactic acid, maleic acid, fumaric acid, succinic acid, methanesulfonic acid, benzenesulfonic acid, benzoic acid, p-toluenesulfonic acid, oxalic acid, p-nitrobenzoic acid, salicylic acid or 4-chlorobenzoic acid.
 16. A process according to claim 1, wherein step e) is performed in tetrahydrofuran at reaction temperature range between 10° C. and 30° C.
 17. A process according to claim 1, wherein step f) is performed in an organic solvent with acid catalyst in temperature range between 0° C. and 100° C.
 18. A process according to claim 1, wherein step g) is performed in an organic solvent with acid in temperature range between 0° C. and 100° C.
 19. A process according to claim 3, wherein step a) is performed with an oxidant at a reaction temperature range between 15° C. to 25° C.
 20. A process according to claim 4, wherein the solvent is a co-solvent of water and acetonitrile.
 21. A process according to claim 5, wherein the oxidant is a co-oxidant of 2,2,6,6-tetramethylpiperidinooxy and sodium hypochlorite.
 22. A process according to claim 6, wherein step b) is performed with an azide reagent and a base in an organic solvent and followed by adding an alcohol at temperature of 80° C.
 23. A process according to claim 6, wherein the base used in step b) is 4-methylmorpholine.
 24. A process according to claim 6, wherein the solvent used in step b) is toluene.
 25. A process according to claim 6, wherein the alcohol used in step b) is 4-methoxyphenylmethanol.
 26. A process according to claim 1, wherein step c) is performed with an amination agent, at reaction temperature range of 25° C. and 30° C.
 27. A process according to claim 13, wherein step d) is performed in a solvent with an organic or inorganic acid at a temperature range of 15° C. and 25° C.
 28. A process according to claim 14, wherein the solvent used in step d) is methyl tert-butyl ether.
 29. A process according to claim 13, wherein the acid used in step d) is 4-chlorobenzoic acid.
 30. A process according to claim 17, wherein step f) is performed in an organic solvent with acid catalyst in temperature range between 60° C. and 80° C.
 31. A process according to claim 1, wherein step g) is performed in an organic solvent with acid in temperature range between 10° C. and 40° C. 